DK150602B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO DERIVATIVES OF 3-ALKYL-5- (2-HYDROXY-STYRYL) -ISOXAZOLES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS - Google Patents

Description

150602

The present invention relates to an analogous process for the preparation of alkylamine propanol derivatives of 3-alkyl-5- (2-hydroxy-styryl) -isoxazole or physiologically acceptable acid addition salts thereof of the kind set forth in the preamble to the claim, which compounds can be used as valuable drugs. in the treatment of hypertension, coronary heart disease and heart rhythm disorders. The compounds are novel.

It has been found that compounds of the general formula I

R 'i o' ^ V ^ 'nhr

OH

wherein R represents an alkyl group of 1-8 C atoms, an alkenyl or alkynyl group of 2-8 C atoms, a cycloalkyl group of 3-8 C atoms in the ring, and R 1 represents an alkyl group of 1-4 C atoms, or physiologically acceptable acid addition salts thereof, exhibit valuable pharmacological properties.

The compounds can be characterized as pharmacodynamically highly active β-sympatholytics with acute blood pressure lowering or antihypertensive effect. This type of effect is unusual in itself, since known i3 sympatholytics, e.g. propranolol, only acts antihypertensive on longer-term administration.

Due to the aforementioned effects, the present compounds are particularly pharmacotherapeutically useful in the treatment of hypertension, coronary heart disease and heart rhythm disorders.

150602 2

Among the alkyl groups, those containing a branching at the α-standing carbon atom to the amine nitrogen are preferred. Preferred alkyl groups are isopropyl and tert-butyl.

Cycloalkyl groups are, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclopropyl group is preferred.

As alkyl groups for R 'having 1-4 C atoms that are straight or branched can be mentioned methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Of this, methyl and ethyl are preferred.

The process of the invention is characterized by reacting a 3-alkyl-5-styryl-isoxazole of the general formula II

_ R *

^ O-CH2-A

Wherein A represents the group

O OH

/ \ and / or I

-CH - CH2 -CH-CH2-B, wherein B represents a nucleophile cleavage group and R 'is as defined in formula I, with an amine of the general formula H 2 N-R, R 3 wherein R is as in formula I of meaning, conveniently in a solvent and optionally in the presence of an acid binding agent, at temperatures of from 10 to 120 ° C and optionally transferring the thus obtained compound to an acid addition salt with a physiologically acceptable acid.

The leaving group B preferably represents a halogen atom, especially chlorine, bromine or iodine. Further, for example, aromatic or aliphatic sulfonic acid groups are considered as nucleofuge cleavage groups, e.g. the p-toluenesulfonic acid, p-bromobenzene sulfonic acid or methanesulfonic acid group.

The reactions are carried out at temperatures of 10 to 120 ° C, ie. at room temperature or at higher temperatures, preferably at temperatures of 50 to 120 ° C. The reaction may be carried out under atmospheric pressure or in a closed container under elevated pressure, optionally under heating to the specified temperature range.

Especially with slightly volatile amines H2N-R it may be advantageous to carry out the reaction in a closed system, ie. in an autoclave.

The starting compounds can be reacted directly, that is, without the addition of a diluent or solvent. Conveniently, however, the reactions are carried out in the presence of an inert diluent or solvent, e.g. a lower alcohol having 1-4 C atoms such as methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether such as e.g. diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene itself, or an alkylbenzene, especially toluene or xylene, or an aliphatic hydrocarbon such as hexane, heptane or octane, a lower aliphatic ketone such as acetone, methylethyl ketone or methyl isobutyl ketone, a dialkylformamide, such as dimethylformamide or diethylformamide, in the presence of dimethylsulfoxide or of water or in mixtures of the above solvents.

The amine of formula E EN-R used in excess is optionally suitable as a solvent or diluent.

Preferred solvent in the reaction of 3-alkyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazoles with an amine R-NE 2 are lower alcohols, especially ethanol or isopropanol, the reaction being preferably carried out at temperatures of 50 to 120 ° C. Optionally, the reaction may be carried out in a closed container under pressure, especially if lower boiling amines are used. In the nucleophilic substitution of a group B, a lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a cyclic aliphatic ether, especially tetrahydrofuran or dioxane, or a dialkylformamide, such as dime thylformamide, and temperatures of 90 are preferred. to 120 ° C. Optionally, the reaction may be carried out in the presence of a catalytic amount of sodium or potassium iodide.

It should also be mentioned that a mixture of epoxide with a halogen hydrine is also optionally considered as a starting compound of formula II, since mixtures occur in the technical preparation of the starting compounds in certain circumstances.

In an appropriate embodiment for nucleophilic substitution of group B with the amine used, the reaction is carried out in the presence of a base as an acid binding agent. Preferred bases are alkali metal hydroxides, carbonates, hydrogen carbonates, alcoholates, especially methylates and ethylates, or a tertiary organic amine, such as pyridine or a trialkylamine, such as trimethylamine or triethylamine. Particularly of alkali-crude metal compounds, sodium and potassium compounds are considered. For this, the base is used in a stoichiometric amount or in a slight excess. It may be appropriate to simultaneously use the amine to be converted in excess as an acid binding agent.

The complete reaction depends on the reaction temperature and is usually completed within 2 - 15 hours. The reaction product can be recovered in a conventional manner, e.g. by filtration or distillation of the solvent or diluent from the reaction mixture.

10 is then purified in the usual manner, e.g. by recrystallization by a solvent, transfer to an acid addition compound or by column chromatography.

The starting compounds of formula II may be prepared by alkylation of a 3-alkyl-5- (2-hydroxy-styryl) -isoxazole, such as e.g. is obtained in a Wittig reaction from a di-alkyl-isoxazolyl-5-methylene phosphate and a salicylaldehyde equipped with a protecting group with a protecting group according to DE Publication No. 2,818,998, with an epihalohydrin or an α, ω-dihalo-2-propanol.

As epihalohydrin, epichlorohydrin, epibromohydrin and epioiodohydrin are considered, and as α, α / -dihalogen-2-propanol especially 1,3-dichloro-2-propanol and 1,3-dibromo-2-propanol are considered.

The reaction of 3-alkyl-5- (2-hydroxy-styryl) -isoxazole to prepare the starting compounds of formula IX is conveniently carried out at temperatures of 0 to 120 ° C and at normal pressure or in a closed container under elevated pressure. The reaction is conveniently carried out in an inert diluent or solvent, e.g. a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, in a lower alcohol having 1-4 C atoms, such as methanol, ethanol, propanol or butanol, in a lower aliphatic or cyclic ether such as diethyl ether, tetrahydrofuran or dioxane, in a dialkylformamide, such as dimethylformamide or diethylformamide, or in dimethylsulfoxide and hexamethylphorphoramide, or with excess of the alkylating agent as a diluent or solvent.

Preferably, the reaction is carried out in the presence of a base as an acid binding agent. Suitable bases are alkali metal carbonates, hydrogen carbonates, hydroxides, hydrides or alcoholates, especially of sodium and potassium, basic oxides, such as alumina or calcium oxide, organic tertiary bases, such as pyridine, piperidine or a lower trialkylamine, such as trimethyl or triethylamine. For this purpose, the bases can be used in a ratio of the alkylating agent used in catalytic amount or in stoichiometric amount or in a small excess.

Preferably, the 3-alkyl-5- (2-hydroxy-styryl) isoxazole is reacted with epibromohydrin or 1,2-dibromopropanol-2 in a polar aprotic solvent, especially dimethylsulfoxide, in the presence of at least one molar equivalent base, especially sodium hydride. calculated on alkylating agent, at temperatures of from 0 to 50 ° C.

Analogous to the process described for the reaction of phenol with 1,3-dichloro-2-propanol described in Liebigs Annalen der Chemie 1976, pages 221 'to 224, 3-alkyl-5- (2-hydroxy-styryl) -25 isoxazole can also be reacted. with the equivalent amount of 1,3-dichloro-2-propanol in aqueous baking soda at temperatures around 50 ° C.

Starting compounds of the general formula II wherein A represents the group / ° / -CH - CH2

can also be obtained by reacting methane phosphonic acid ester of the general formula VI

RHch 2 <0 ° 2115 with that of J. Chem. Soc. London, 1974, 1571-1577 described o- (2,3-epoxypropoxy) -benzaldehyde. In reaction of o- (2,3-epoxypropoxy) -benzaldehyde with a phosphorane of formula VI, inert organic solvents are considered as reaction medium, e.g. a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ethers, such as diethyl ether, 1,2-10 dimethyloxyethane, tetrahydrofuran or dioxane, benzene or an alkylbenzene, such as toluene or xylene, an aliphatic hydrocarbon such as hexane, heptane or octane, di -methylsulfoxide, dimethylformamide or mixtures of said solutions. The reaction is carried out between 0 ° C and the boiling temperature of the solvent used, preferably at room temperature, over 1 to 48 hours, preferably 1 to 16 hours, and preferably in a nitrogen atmosphere. Suitable bases for this Wittig-Horner reaction are alkali metal hydrides, amides or alcoholates, especially of sodium and potassium, preferably sodium methylate is used.

The present compounds of formula I have at the aliphatic side chain carbon atom 2 a chiral center and they can be obtained as racemates which by well known methods, e.g.

25 by forming diastereomeric salts with optically active auxiliary acids, such as dibenzoyl acid, campher-10-sulfonic acid, ditoluyl tartaric acid or 3-bromo-campher-8-sulfonic acid, can be separated into the optically active antipodes.

8

Optionally, the obtained compounds are transferred into the acid addition salt with a physiologically acceptable acid.

As usual physiologically acceptable organic or inorganic acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid are considered and as organic acids, e.g. oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzoic acid, or they can be obtained from Fortschritte der Arzneimittelforschung, 10 vol. 10, pages 224 to 225, Birkhåuser publishers, Basel and Stuttgart, 1966, or from the Journal of Pharmaceutical Sciences, Vol. 66, pages 1 to 5 (1977).

The acid addition salts are usually obtained in a manner known per se by mixing the free base or solutions thereof with the appropriate acid or solutions thereof in an organic solvent, e.g. in a lower alcohol such as methanol, ethanol or propanol, or in a lower ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or in an ether such as diethyl ether, tetrahydrofuran or dioxane. For better separation of crystals, mixtures of the aforementioned solvents may be used. In addition, pharmaceutically acceptable aqueous solutions of the acid addition compounds of the aminopropanol derivative of the general formula I can be prepared by dissolving the free base of the general formula I in an aqueous acid solution.

The study for the pharmacodynamic properties of the compounds of the invention was carried out according to the following methods: 30 in. Β-sympatholytic effect on isoproterenol-tachycardia in anesthetized cats.

Intravenous administration of 0.001 mg / kg of the β-sympathomimetic isoproterenol increases the heart rate of ba standard cats (weight 2-4 kg) in hexobarbital anesthesia (200 mg / kg intramuscularly) with an average of 61 strokes (40%).

β-sympatholytics specifically inhibit this frequency increase and dose-dependence. The administration of the compounds to be tested occurs 10 minutes before isoproterenol to groups of 3 to 5 cats per day. dosage.

As ED 50%, indicate the dose which inhibits isoproterenol tachycardia by 50%.

2. Blood pressure lowering effect on narcotic rats.

10 For a study of the blood pressure lowering effect, groups of 3 to 5 male Sprague-Dawley rats (weight: 230-280 g) in urethane anesthesia (1.78 g / kg intraperitoneally) were administered intravenously.

The blood pressure in A.carotis is measured over a Statham transducer.

As ED 20%, indicate the dose which lowers mean carotid pressure by 20%.

3. Antihypertensive effect on spontaneously hypertonic rats. The compounds are administered orally to groups of 8 male, 25 spontaneously hypertonic Okanoto rats (weight: 280 - 350 g).

Before and 2 hours after administration, the systolic blood pressure on the rat tail is measured unsteadily by piezocrystals.

As ED 20%, taking into account the value of untreated controls, the dose that lowers systolic pressure by 20% is determined.

Acute toxicity in mice.

To determine the acute toxicity (LD 50), the compound is administered intraperitoneally to groups of 10 female NMRI mice (weight 19-20 g). The study path was 1 week.

5 The calculation of the effective doses (methods 1-3) was based on regression analysis of the linear relationship between the dose logarithm and the effect. LD 50 (Method 4) was determined by probit analysis. As the reference compound, the known β-sympatholytic propanolol was used.

As shown in Table 1, the β-sympatholytic effect of the compounds of Examples 1, 3, 6 and 13 is 6.1 to 20 times higher than that of the known β-sympatholytic propranolol. The compound of Example 15 is approximately equal to the effect of propranolol.

In addition to this effect, the compounds of this invention cause an acute lowering of arterial blood pressure.

After administration of 0.4 mg / kg of Example 3, a blood pressure drop of 20% is seen on average in the rat. Similarly, the compounds of Examples 1, 5, 6 and 13 lower blood pressure at doses between 0.65 and 1 mg / kg (ED 20%). In contrast, propranolol acts to increase blood pressure in rats up to doses of 2.15 mg / kg.

First, the sublethal dose 4.64 mg / kg lowers the pressure by an average of 36%. About twice the dose (10 mg / kg) kills 2 out of 6 animals. After administration of 10 mg / kg of the compound of Example 6, 1 in 6 animals dies. However, this dose is 25 times greater than the blood pressure lowering dose (0.4 mg / kg).

As in Example 3, it was shown that the compounds also act to lower blood pressure after oral administration in spontaneously hypertonic rats. 14.5 mg / kg lowers elevated blood pressure by an average of 20%. In this experiment, propranolol is ineffective until a dose of 100 mg / kg.

The lethal dose (LD 50, mouse, intraperitoneal) of the compound of Example 3 (123 mg / kg) is somewhat higher, from Example 13 the lethal dose is more than twice the lethal dose of propranolol (108 mg / kg). For the compounds of Examples 1, 5 and 6 are just as toxic and somewhat more toxic than propranolol. Given the high activity (Examples 1 and 6) or the all new effect type, this finding is irrelevant.

TABLE 1

Ex. β-sympatholytic Blood pressure lowering No. effect 1) effect 2) Lethality 4) _ED 50% RW_ED 20% _LD 50 1 0.0077 14.3 (0.65 108 15 3 0.0055 20.0 0.40 123 5 0 , 12 0.9 0.83 95 6 0.018 6.1 0.93 84 13 0.017 6.5 1.00 247

Propranolol 0.11 1.0 3) 108 20 1) Cats. Hexobarbital anesthesia. Application: intravenous.

ED 50% = Dose mg / kg, which inhibits the increase in heart rate of isoproterenol by 50%. R.W. = relative effect. Propranolol = 1.00.

2) Rats. Urethane anesthesia. Application: intravenous.

25 ED 20% = Dose mg / kg lowering blood pressure by 20%.

3) Up to 2.15 mg / kg blood pressure rise (11%); 4.64 mg / kg blood pressure lowering (36%); 10 mg / kg 2/6 animals die.

4) Mouse. Administration: Intraperitoneal LD 50 (mg / kg) 12 Due to their action, the following compounds in particular should be highlighted: 3-methyl-5- [2- (2-hydroxy-3-isopropylamino-propoxy) -styryl] -isoxazole, m.p. . 106-108 ° C; 3-methyl-5- [2- (2-hydroxy-3-tert.-butylamino-propoxy) -styryl] -isoxazole, m.p. 83-85 ° C; 3-Ethyl-5- [2- (2-hydroxy-3-tert.-butylamino-propoxy) -styryl] -isoxazole, m.p. 163-164 ° C; 3-ethyl-5- [2- (2-hydroxy-3-cyclopropylamino-propoxy) -styryl] -

Isoxazole, m.p. 137-139 ° C

3-methyl-5- [2- (2-hydroxy-3- (3-methyl-1-butyn-3-ylamino) -propoxy-styryl] -isoxazole, mp 191 ° C.

The process according to the invention is further explained in the following embodiments.

22 Manufacture of Pre-Products.

Compound I: o- (α-Methoxy-ethoxy) -benzaldehyde.

a) 610 g (5 moles) of salicylaldehyde are dissolved in 1.5 liters of xylene.

To this solution is added dropwise at 40 - 50 ° C 900 g (5 moles) of a 30% NaOCH 2 solution in methanol.

20 is then heated and the methanol is distilled off, which is gradually replaced in the reaction flask with the same amount of xylene. It is heated for as long as the xylene begins to distill off (about 130 ° C at the distillation transition). Thereafter, the suspension of the sodium salt 25 of the salicylaldehyde is cooled to 60 ° C, and air is further reacted as directed under c).

b) 200 ml of xylene is added to a spatula tip of hydroquinone and cooled to -20 to -30 ° C and 290 g (5 moles) of vinyl methyl ether are added. Then, at -30 ° C

3Q 183 g (5 moles) of HCl, and the solution is allowed to rise as the temperature rises to room temperature. The solution of the obtained 1-chloroethyl methyl ether is further reacted as described under c).

C) The solution of 1-chloroethyl methyl ether described in point (b) is dripped to the 60 ° C hot solution of the sodium salt of salicylaldehyde (see point a), and further stirred for 1.5 hours at 60 ° C, optionally adjusted to a pH of 8 - 9 using 30% NaOCH-j solution and stirred overnight at room temperature.

Then, the precipitated sodium chloride which is washed with xylene is filtered off and the xylene is evaporated on a rotary evaporator. The residue of the residue is distilled over a column at 2 mmHg. 690 g of o- (α-methoxyethoxy) -benzaldehyde are obtained with Kp2: 94-96 ° C.

Compound II: (3-Methylisoxazolyl-5) -methane phosphonic acid diethyl ester 445 g of 5-chloromethyl-3-methylisoxazole and 674 g of phosphoracetic acid triethyl ester are slowly heated to 150 ° C and the solution is kept at this temperature for 4 hours. After distillation, 546 g (69 S of theoretical value) (3-methylisoxazolyl-5 -) - methane phosphonic acid diethyl ester with boiling point 118 - 121 ° C / 0.3 Torr are obtained.

1 H NMR Spectrum (CHCl 3, TMS internal): T-3.85 (d, J = 3 Hz, 1H) 4.17 (m, J = 8 Hz, 4H) 6.67 (d, J = 22 Hz, 2H) 7.72 (s, 3H) 8.67 (t, J = 8 Hz, 6H).

C9H16NO4P (233.21)

Calculated: C 46.35 - H 6.91 - N 6.01 - P 13.28

Found: C 45.9 - H 7.0 - N 6.0 - P 13.0.

Compound III: (3-Ethylisoxazolyl-5) -methane phosphonic acid diethyl ester 3Q 15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethylphosphite nmarmoclantronmf fi 1 15fi®P_ner 14 150602 under reduced pressure. 18.2 g (3-ethyl-isoxazolyl-5) -methane phosphonic acid diethyl ester with boiling point 120 - 121 ° C / 0.2 mmHg (yield 71.2%) are obtained.

1 H NMR Spectrum (CDCl 3, TMS internal): δ T = 3.85 (d, J = 3 Hz, 1H), 4.17 '(m, J = Hz, 4H), 6.60 (d, H = 20 Hz, 2H), 7.35 (q, J = Hz, 2H), 8.50 - 8.93 (m, 9H).

10 C10H18NO4P (247 # 23)

Calculated: C 48.58 - H 7.34 - N 5.67 - P 12.53

Found: C 48.4 - H 7.1 - N 5.7 - P 12.3.

The other phosphone esters were prepared in an analogous manner.

(3-isopropyl-isoxazolyl-5) -methane phosphonic acid diethyl ester 15 Kpg H7 “122 ° C. Yield 73%.

(3-tert.-butyl-isoxazolyl-5) -methane phosphonic acid diethyl ester KpQ 3: 126-132 ° C. Yield 88%.

Preparation of the starting compounds.

EXAMPLE I

20.8 g (0.2 mole) of 55% sodium hydride suspension in paraffin oil are placed in 100 ml of absolute dimethyl sulfoxide. To this, 47 g (0.2 mole) (3-methylisoxazolyl-5) -methylene phosphonate at room temperature is stirred for an additional 30 minutes, then 36 g (0.2 mole) of o- (1-methoxyethoxy) benzaldehyde is added dropwise, then the reaction mixture is allowed to stir at room temperature for 24 hours.

One liter of ice water is added and extracted three times with 80 ml of methylene chloride per ml. walk. The combined organic phases are dried over sodium sulfate and evaporated on rotary evaporator. Dissolve the oily residue in 80 ml of methanol and 10 ml of water and add 2 ml of 5 U HCl and stir for a further 10 minutes. Then excess 5 of water is slowly added to the mixture until a precipitate precipitates. This is extracted, washed with water and recrystallized from ethanol. 19 g (47% of theoretical yield) of colorless crystals, mp 236 - 238 ° C.

C12H11N02 (201)

Calculated: C 71.6 - H5.5 - N 7.0

Found: C 71.8 - H 5.5 - N 6.8

EXAMPLE · II

3-Ethyl-52 (2-hydroxy-styryl) -isoxazole As in Example 1, 6 g (0.02 mole) of diethyl (3-ethyl-isoxazolyl-5) methylene phosphonate are reacted and 4.4 g (0.02 mole) ) o- (1-methoxyethoxy) -benzaldehyde and recrystallized from iso-propanol to give 1.7 g (32% of theory) of colorless crystals.

Melting point: 175 - 176 ° C.

C13H13N02 (215)

Calculated: C 72.5 - H6, l - N 6.5

Found: C 72.5 - H6.2 - N 6.6.

EXAMPLE · III

2 5 -isoprgpy1-5-12-hydroxy-styryizisgxazole

As in Example I, 32 g (0.12 mol) of diethyl (3-iso-propyl-isoxazolyl-5-) -methylene phosphonate and 22 g (0.12 mol) of o- (1-methoxyethoxy) -benzaldehyde are reacted. and recrystallized from toluene. 20 g (73% of theory 30 yield) of colorless crystals are obtained.

Melting point: 129 - 133 ° C.

150602 16 C16H15N02 (229)

Calculated: C 73.3 - Η 6.6 - Ν 6.1

Found: C 73.7 - Η 6.7 - H 5.8.

EXAMPLE IV

5-iterated-butyl-S ^ U-hydroxy-styryl) -isoxazole

35 g (0.13 mole) of diethyl ether is reacted as in Example I. -butyl-isoxazolyl-5) -methylene phosphonate and 23 g (0.13 mol) of o- (1-methoxyethoxy) -benzaldehyde and recrystallized from toluene. 24.8 g (78% of theoretical yield) of 10 colorless crystals are obtained.

Melting point: 152 - 155 ° C.

C15H17NO2 (243)

Calculated: C 74.0 - H 7.0 - N 5.8

Found: C 73.4 - H 7.3 - N 5.5.

EXAMPLE V

11St ^ Yll ^ lI ^ ii ^ iS-epoxyprogoxy ^ -styrYjJ -isoxazole 6.44 g of 55% sodium hydride in paraffin oil (0.15 mol) is placed in 200 ml of absolute dimethyl sulphoxide and added dropwise at room temperature 30 g (0.15 mole) 3-methyl-5- (2-20 hydroxy-styryl) -isoxazole dissolved in 50 ml of dimethyl sulfoxide.

After hydrogen evolution has ceased, 20.2 g (0.15 mole) of epibromohydrin is added dropwise and the reaction mixture is stirred for 20 hours at room temperature. The mixture is added 1.5 liters of ice water and the solid residue is suctioned off and recrystallized from 25 isopropanol. 26.2 g (68% of theoretical yield) of colorless crystals are obtained.

Melting point: 99-100 ° C.

C15H15N03 <257)

Calculated: C 70.0 - H 5.9 - N 5.4 Found: C 70.0 - H 5.9 - N 5.5.

EXAMPLE VI

17 150602 3-θ ^ γ1-5- ^ 2 -_ (2χ3-βροχγρΓθροχγ) _23ΐγΓγ1] _- ΐ3θΧ§ζο1

The compound is prepared analogously to V from 5.1 g of 55% sodium hydride (0.116 mole), 25.0 g (0.116 mole) of 3-5 ethyl 5- (2-hydroxystyryl) isoxazole and 15.9 g (0.116 mol) epibromohydrin. The reaction mixture is poured onto brine and shaken with diethyl ether. The ethereal solution is dried over anhydrous sodium sulfate and evaporated. 29.2 g (93% of theoretical yield) of a colorless oil are obtained.

EXAMPLE VII

3-Isoprgpyl 25-J2- (2β-epoxy-propoxy) -styryz-isoxazole

Prepared analogously to Example VI from 3.4 g of 55% sodium hydride (0.078 mol), 18 g (0.078 mol) of 3-isopropyl-5-15 (2-hydroxystyryl) -isoxazole and 10.8 g (0.078 mol) of epibromohydrin . 21.5 g (97% of theoretical yield) of a colorless oil were obtained.

EXAMPLE VIII

Prepared analogously to Example VI from 3.8 g of 55 percent sodium hydride (0.086 mole), 21 g (0.086 mole) of 3-tert.-butyl-1-yl. 5- (2-hydroxystyryl) -isoxazole and 11.8 g (0.086 mole) of epibromohydrin. 25.0 g (97% of theoretical yield) of a colorless oil were obtained.

EXAMPLE IX

1.0 g of 3-methyl-5- [2- (2,3-epoxypropoxy) styryl] -isoxazole is dissolved in 20 ml of 3-N-ethereal hydrogen chloride solution and the mixture is allowed to stand for 12 hours at room temperature.

The resinous portion formed is separated and chromatographed with chloroform over silica gel. The product eluate is evaporated to dryness in vacuo and the resulting crude extract is recrystallized from an acetone-cyclohexane mixture. NMR spectroscopically pure (3-methyl-5- [2- (2-hydroxy-3-chloro-propoxy) -styryl) -isoxazole) is obtained, m.p. 67-68 ° C.

1 H-NMR spectrum (CDCl3, TMS internal).

2.30, 3.15 (m, 6H) δ 3r92 (s, 1H) 5 / 60-5.92 (m, 3H) 6.24 (d, J = 3.5 Hz, 2H) 6.77 ( wide s, OH).

Preparation of the compounds of the invention: EXAMPLE 1 3 III 1-Ethyl-52 [2-j (2-hydroxy-3-isopro2yl-airinogropoxy) -styryl] -isoxazole 3.4 g (0.013 mol) 3-methyl-5 - [2- (2,3-epoxy-propoxy) -styryl] -isoxazole and 2.3 g (0.039 mol) of isopropylamine are heated at reflux for 8 hours in 50 ml of isopropanol. After cooling, the reaction solution is filtered and evaporated on rotary evaporator. 3.8 g of solid residue are obtained which are recrystallized from toluene. 2.4 g (58% of theoretical yield) of colorless crystals are obtained.

Melting point: 106 - 108 ° C.

C18H24H2 ° 3 (316'4)

Calculated: C 68.3 - H 7.6 - N 8.9

Found: C 68.4 - H 7.6 - N 9.0.

EXAMPLE 2 3-Methyl-5-J [2- (2-hydroxy-3-cycloprogylarciinopropoxy) _-styryl] -3 isoxazole

Prepared analogously to Example 1 from 5.0 g (0.019 mole) of 3-methyl-5- [2- (2,3-epoxypropoxy) -styryl] isoxazole and 1.21 g (0.2 mole) of cyclopropylamine. From toluene 2.4 g (40% 30 of theoretical yield) of colorless crystals with melting point 108 DEG-109 DEG C. are obtained.

C18H22N2 ° 3 (314/4)

Calculated: C 68.8 - H 7.1 - N 8.9

Found: C 6 8.8 ~ H 7.0 ~ N 8.9.

EXAMPLE 3 (iS ^ i'hxilSlIl (hydroxyl) S-tert-butylaminogrogoxy) -styryl] -isoxazole

Prepared analogously to Example 1 from 5.0 g (0.019 mole) of 3-methyl-5- [2- (2,3-epoxypropoxy) -styryl] isoxazole and 1.56 g (0.2 mole) of tert. -butylamine.

3.1 g (48% of theoretical yield) of colorless crystals, mp 83-85 ° C) C19H27N2 ° 3 '°' 5 H2 ° <339'4>

Calculated: C 67.3 - H 8.0 - N 8.3 Found: C 67.2 - H 7.9 - N 8.1.

30 g of crude 3-methyl-5- [2- (2-hydroxy-3-tert.-butylaminopropoxy) -styryl] isoxazole are dissolved in a little ethanol and added dropwise to ethereal hydrogen chloride solution dropwise. The precipitated 3-methyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) -styryl] -isoxazole hydrochloride is suction washed, washed with dry ether and recrystallized twice with methanol-ether mixture (volume). 1: 1) and dried.

Yield 33.8 g (79% of theory), mp 217 ° C.

C19H2703N2C1 (367)

Calculated: C 62.2 - H 7.4 - N 7.6 - Cl 9.7

Found: C 62.1 - H 7.3 - N 7.7 - Cl 9.8.

Similarly, with the ethereal fumaric acid, the fumarate of EXAMPLE 4 is obtained, m.p. 188 ° C.

3iethyl-M2-j2-hydroxy = 3-iso2ro2ylamino2roxyoxyl) styryl] -isoxazole 5 Prepared from 7 g (0.026 mol) of 3-ethyl-5- [2- (2,3-epoxy-propoxy) styryl] -isoxazole and 2 µg of isopropylamine (0.04 mol) in 100 ml of isopropanol. 8.1 g of an oil are dissolved in 100 ml of isopropanol and ethereal hydrochloric acid is added. The precipitated crystals are aspirated and dried.

4.9 g (50% of theoretical yield), mp 134-135 ° C.

C19H25ClN2 ° 3 (366.9)

Calculated: C 62.7 - H 7.4 - N 7.6 - Cl 9.7 Found: C 61.9 - H 6.9 - N 7.7 - Cl 9.6.

EXAMPLE 5 3-Methyl-512- (2-hydroxy-3-cyclopropylaminopropoxy) -styrryl-isoxazole-7 g (0.026 mol) 3-ethyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazole and 2, 3 g of cyclopropylamine (0.04 mol) is reacted analogously to Example 1 in 100 ml of isopropanol. 8.6 g of an oil is separated on a column (55 x 5 cm) of silica gel 60 (0.063 - 0.20 mm) from the Merck factories to remove contaminants. The eluent is a 9: 1 mixture of methylene chloride and methanol. The fractions are tested for purity by thin layer chromatography. There is obtained 3.2 g of an oil which is dissolved in 40 ml of isopropanol and a little ether, which is precipitated with 1.1 g of fumaric acid dissolved in hot isopropanol. The crystals are aspirated and dried.

2.1 g (21% of theoretical yield), mp 137 -30 139 ° C.

150602 21 C22H26N2 ° 5 (386'5)

Calculated: C 65.2 - H 6.7 - N 7.2

Found: C 64.7 - H 6.8 - N 7.5.

EXAMPLE 6 3-Ethyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) styryl] -isoxazole 7 g (0.026 mol) of 3-ethyl-5- [2- (2,3-epoxypropoxy) -styryl] -isoxazole and 3.0 g (0.04 mole) of tert-butylamine are reacted analogously to Example 4. 6.6 g (66% of theoretical yield) 10, mp 163 - 164 ° C.

C20H29C1N2 ° 3

Calculated: C 63.1 - H 7.7 - N 7.3 - Cl 9.3

Found: C 62.9 - H 7.5 - N 7.2 - Cl 9.2.

EXAMPLE 7 3li§2EE2EYil3li2li2l3iiY ^ E22Yl2li22EE2E ¥ i2i2i22Ei-2E25Yil§i: yl yl isoxaz2l 7 g (0.025 mol) 3-isopropyl-5- [2- (2,3-epoxypropoxy) styryl] -isox] (0.05 mole) of isopropylamine is reacted analogously to Example 1.

20 of toluene 5.9 g (68% of theoretical yield) of colorless crystals having a melting point 87 - 88 ° C are obtained.

C20H28N2 ° 3 (344'5>

Calculated: C 69.7 - H 8.2 - N 8.1

Found: C 69.9 - H 8.2 - N 8.1.

EXAMPLE 8 22 (2-Hydroxy-3-cycloprogylaminogro20XY) - γTY 2 Y 2 S 22 22 S 7 g (0.025 mol) 3-isopropyl-5- [2- (2.3 epoxypropoxy) styryl-5-isoxazole and 3.0 g (0.05 mole) of cyclopropylamine are reacted analogously to Example 5. 3.0 g (30% of theoretical yield) of colorless crystals are obtained as fumarate, mp 148-152 ° C.

C22H28N2 ° 5 (400'5) Calculated: C 66.0 - H 7.0 - H 7.0

Found: C 65.7 - H6.8 - N 7.0.

EXAMPLE 9 - Lisopropyl-S - 3 - tert -hydroxy-S-tert-butylaminoprogoxyl-styryl-isoxazole 7 g (0.025 mol) 3-isopropyl-5- [2- (2,3-epoxypropoxy) styryl] isoxazole and 3.6 g (0.05 mole) of tert-butylamine are reacted analogously to Example 4. 5.8 g (59% of theoretical yield) of colorless crystals having a melting point of 191 -193 ° C are obtained.

2 ° C21B31C1N2O3 (394.9)

Calculated: C 63.9 - H 7.9 - N 7.1 - Cl 9.0

Found: C 64.1 - H 8.0 - N 6.9 - Cl 9.1.

EXAMPLE 10 3-tert.-butyl-5- [2- (2-hydroxy-3-isopropylaminopropyl) -styryl] -isoxazole 7 g (0.023 mol) of 3-tert-butyl-5 - [2- (2) , 3-Epoxypropoxy) -styryl] -isoxazole and 2.8 g (0.05 mole) of isopropylamine are reacted analogously to Example 5. 2.5 g (27% of theoretical yield) of colorless crystals are obtained as fumarate with the melting point 30 192 - 194 ° C.

C25H34N2 ° 5 (474'6)

Calculated: C 66.3 - Η 7.6 - Ν 6.7

Found: C 66.5 - Η 7.8 - Ν 6.6.

EXAMPLE 11 5-tert-butyl-5 - 6-g-hydroxy-5-cyclogroglylininoprogoxyl-7 g (0.023 mol) 3-tert-butyl-5- [2- (2,3-epoxypropoxy) styryl] -isoxazole and 2.7 g (0.047 mol) of cyclopropylamine are reacted analogously to Example 1. 5.8 g of oil are dissolved in diethyl ether and precipitated with 2 g of oxalic acid dissolved in a little ethanol. 2.7 g (26% of theoretical yield) of colorless crystals are obtained, mp 170 - 174 ° c.

C23H30N2 ° 7 (446'5)

Calculated: C 61.9 - H 6.8 - H 6.3 Found: C 62.9 - H 7.0 - N 6.2.

EXAMPLE 12-Zt-IIIl-tyl-5- [2-j2-Hydroxy-3-tert-butylaminopropoxy] -7 g (0.023 mol) 3-tert-butyl-5- [2- (2,3- epoxypropoxy-20 styryl] -isoxazole and 3.4 g (0.047 mole) of tert.-butylamine are reacted analogously to Example 4. 6.8 g (72% of theoretical yield) of colorless crystals having a melting point of 207-208 ° are obtained. C.

C22H33C11J2 ° 3 (408'9) Calculated: C 64.6 - H 8.1 - Cl 8.7 - N 6.9

Found: C 64.2 - H 8.0 - Cl 8.6 - N 6.7.

Example 13 24 3-Methyl-5-β-2- (2-hydroxy-3- (3-methyl-1-butyn-3-ylamino) -propoxy) -styryl] -isoxazgl 5 g (0.019 mol) methyl 5- [2- (2,3-epoxypropoxy) -styryl] -5-isoxazole and 1.7 g (0.02 mol) of 3-methyl-3-amino-butyne-1 are reacted analogously to Example 3 and transferred as described in the hydrochloride example.

Yield: 3.5 g (49% of theory) with mp 191 ° C.

C20H25N2C1O3 (376'9)

Calculated: C 63.7 - H 6.7 - N 7.4 - Cl 9.4

Found: C 63.7 - H 6.8 - H 7.7 - Cl 9.5.

EXAMPLE 14 3-Methyl-5- [2- (2-hydroxy-3-tert.-butylaminopropoxy) -styryl] -15

In an autoclave, 2.4 g of 3-methyl-5- [2- (2-hydroxy-3-chloropropoxy) -styryl] -isoxazole, 10 ml of tert, butylamine and 50 ml of dioxane are heated to 100 ° C for 10 hours. After distilling off the volatile portion in vacuo, the high viscous crude extract is shaken in 20 ether-2N sulfuric acid, the water phase is gently adjusted with 4N

baking soda and finally extracted with ether. After drying the organic phase over sodium sulfate, the solvent is removed and the residue is transferred as described in Example 3 into 3-methyl-5- [2- (2-hydroxy-3-tert-butylaminopropoxy) -styryl] -isoxazole hydrochloride, mp 216 - 218 ° C.

Claims (2)

15060: Patent Claims: Analogous Process for Preparation of Amino Derivatives of 3-alkyl-5- (2-hydroxy-styryl) -isoxazoles of general formula I OH 5 wherein R represents an alkyl group having 1 to 8 C atomic inheritance an alkenyl or alkynyl group having 2 to 8 C atoms or a cycloalkyl group having 3 to 8 C atoms in the ring, and R 1 represents an alkyl group having 1 to 4 C atoms, or physiologically acceptable acid addition salts thereof, characterized by reacting a 3- alkyl-5-styryl-isoxazole of the general formula II-R * (3χχο / 11 O-CH2-A wherein A represents the group / R -CH - CH2 and / or -CH-CH2-B, B being a nucleophile leaving group and R 'having the meaning given above in formula I, with an amine having the general formula h2n-r,